6,6-difluoro-17{62 -hydroxy-17{60 -ethynyl-4-estren-3-one and 6,6-difluoro-13{62 -ethyl-17{62 -hydroxy-17{60 -ethynyl-4-gonen-3-one ethylene

ABSTRACT

6,6-Difluoro-17 Beta -hydroxy-17 Alpha -ethynyl-4-estren-3-one ethylene ketal (6,6-difluoronorethindrone ethylene ketal), which can be obtained i.a. by a reaction of 6,6-difluoro-4-estren-3,17dione 3-ethylene ketal with either ethynylmagnesium bromide or sodium acetylide, is an active progestational and antiuterotrophic agent. Its biological activity in rabbits and mice is comparable to that of norethindrone. Similarly, 6,6difluoro-13 Beta -ethyl-17 Beta -hydroxy-17 Alpha ethynyl-4gonen-3-one ethylene ketal, obtained by reaction of the corresponding 3,17-dione 3-ethylene ketal with acetylene and lithium acetylide, is active.

United States Patent 1111 3,621,010

72 inventor GeorgeAlben Boswell,Jr. 50 FieldofSearch [Machine Wilmington, Del. Searched Steroids 21 AppLNo. 31,763

221 Filed Apr. 24, 1910 1 References cm 451 Patented Nov. 16, 1911 UNITED STATES PATENTS 1 Assisnce E-l-duPonldeNemoumndcomplny 3,2l9,673 ll/l965 Boswell 260/3973 Wllmlngton, Del.

Contlnuatlon-ln-part of application Ser. No. 720,493, Apr. ll, 1968, now Patent No. 3,51 1,861, Continuation-impart 01 application Ser. No. 5,139, Jan. 22, 1970. This application Apr. 24, 1970, Ser. No. 031,763

[54] 6,6-DlFLU0R0-l7B-HYDROXY-l7a1-ETI-lYNYL-4- ESTREN-S-ONE AND 6,6-DIFLUOR0- l 3B-ETl-lYL- 1 7B-l-lYDROXY-l7a-ETHYNYL4-GONEN-3-ONE ETHYLENE 3 Claims, No Drawings [52] U.S. Cl ..260/239.55, 260/3973, 260/3914, 260/397.5, 260/999 Primary Examiner-Henry A. French Anurney-James H. Ryan ABSTRACT: 6,6-Difluoro-l 7/3-hydroxyl 7a-ethynyl-4-estren-3-one ethylene ketal (6,6-difluo1'ono1'ethindrone ethyl- 6,6-DIFLUORO- l 7B-IIYDROXY- l 7a-E'l'l-IYNYL-4- ESTREN-B-ONE AND 6,6-DIFLUORO- I 3 B-ETHYL- 1 7B- IIYDROXY- l 7a-ETl-IYNYL-4-GONEN-3-ONE ETIIYLENE CROSS-REFERENCE TO RELATED APPLICATIONS This is a continuation-in-part of applications Ser. No. 720,493, filed Apr. 1 l, 1968 and now allowed as US. Pat. No. 3,51 L861, and Ser. No. 5,139, filed Jan. 22, 1970.

BACKGROUND OF THE INVENTION This invention is related to the steroid compounds 6,6- difluorol 7B-hydroxyl 7a-ethynyl-4-estren-3-one ethylene ketal, and 6,6-difluorol 3B-ethyl l 7B-hydroxyl 7a-ethynyl- 4-gonen-3-one ethylene ketal which have valuable progestational and antiuterotrophic properties.

The parent applications Ser. No. 720,493 discloses new steroid compounds derived from 6,6-difluoro-I7a-ethynyI-I7B- hydroxy-4-estren-3-one. Example 3 of said parent application describes the synthesis of 6,6-difluoro-l7a-ethynyl-4-estrene- 33,17B-diol. Step .I of that multistep synthesis describes the preparation of 6,6-difluorol 7a-ethynyl-I 7B-hydroxy4-estren-3-one (6,6-defluoronorethindrone). An intermediate in this reaction is 6,6-difluoro-l7B-hydroxy-l7a-ethynyl-4-estren-3-one ethylene ketal from which 6,6-difluoronorethindrone is obtained by hydrolysis with 90 percent acetic acid. The parent application Ser. No. 720,493 does not report any biological properties of this compound.

The parent application Ser. No. 5,139 discloses in step J of example 1 6,6-difluorol 3Bethyl-l7Bhydroxy-l7a-ethynyl-4- gonen-3-one 3-ethylene ketal, the l3-ethyl homolog of the above-mentioned 6,6-difluorol 7B-hydroxyl 7a-ethynyl4- estren-3-one ethylene ketal. Again, no biological properties of the I3-ethyl steroid are reported.

US. Pat. No. 3,219,673 (to Boswell) discloses in example 6 the ethylene ketal of l7a-ethynyl-6,6-difluoro-4-androstene 3-one-l7B-0l from which the free compound (6,6- difluoroethisterone) is obtained by hydrolysis with aqueous hydrochloric acid. No biological properties of this compound are disclosed in the patent.

SUMMARY OF THE INVENTION According to this invention, it has now been discovered that 6,6-difluorol 7cs-hydroxyl 7a-ethynyl-4-estren-3-one ethylene ketal and 6,6-difluoroI3B-ethyl-l7B-hydroxy-l7aethynl-4-gonen-3one ethylene ketal have valuable biological properties. In particular, these compounds have progestational activity in rabbits and antiuterotrophic activity in mice of the same magnitude as the commercial material norethindrone. The novel compounds of this invention can be represented by the following formula I:

in which R is methyl or ethyl.

DETAILED DESCRIPTION OF THE INVENTION The novel l3-methyl steroid compound of this invention can be conveniently prepared either by ethynylation and simultaneous reduction of 6,6-difluoro-4-estrene-3,l7-dione 3-ethylene ketal or by ketalization of 6,6-difluoro-norethindrone. Both these starting materials are described in the parent application Ser. No. 720,493, example 3. Steps I and J. The preparation of this new compound is now illustrated by examples 1 and 2. The l3ethyl steroid compound of this invention is obtained by the procedure of example 3.

EXAMPLE 1 Preparation of 6,6-difluorol 3B-ethyll 7fl-hydroxy- 1 7aethynyl-4-estren-3-one ethylene ketal from 6,6-dilluoro-4- estren-3,l7-dione 3-ethylene ketal A mixture of 6,6-difluoro-4-estren-3,l7-dione 3-ethylene ketal (2) (33.0 g.) and dimethyl sulfoxide (400 ml.) was stirred under nitrogen at 25 C., and treated with a 20 percent (w/v) suspension of sodium acetylide in xylene (250 ml.). After 30 min., the mixture was poured into ice water, saturated with NaCl, and extracted with CI-I,Cl,. The extracts were washed with brine, dried, and evaporated to leave the crude product (I). The same product was obtained when the ketal (2) was treated with ethynylmagnesium bromide or acetylene and potassium t-amylate, but the sodium acetylide method was the most convenient preparation.

EXAMPLE 2 Preparation of 6,6-difluoro- I 3l3-ethyll 7B-hydroxyl 7aethynyl-4-estren-3-one ethylene ketal from l7B-hydroxy 6,6-

difluorol 7a-ethynyl-4-estren-3-one (6,6-

difluoronorethindrone) "CECH "CECH A pure sample of l7a-hydroxy-6,6-difluoro-l7a-ethynyl-4- estren-3-one (3) (0.5 g.) in a mixture of benzene (25 ml.), oxalic acid dihydrate (0.5 g.) and redistilled ethylene glycol (2.5 ml.) was heated under reflux for 3 hours using a Dena-Stark trap, the progress of the reaction being followed by thin-layer chromatography (3:1 v/v ethyl acetate-cyclohexane; R, of compound 3=0.57; R, of compound l=0.62) and the disappearance of the 1.680 cm) band in the IR spectrum. The benzene solution was washed with saturated NaHCO and water, dried, and evaporated to leave the crude ketal (l) as a solid which was recrystallized from a mixture of chloroform, (5 ml.), hexane (5 ml.) and pyridine (I drop). Pure ketal 1) Kill.

3,450 (OH) and 3.3 10 cm." (C CH). a 37 (c 0.6 5. ture was stirred for 16 hours. The mixture was poured into ice CHCl H nmr 6=36l (d J=4) (4-H), 240 (d J=l) (ketal), water (500 m1.) and the solid (8.4 g.) removed by filtration.

154 (s) (C CH), and 53 Hz. (s) (18-1-1). Crystallization from aqueous methanol gave the l7B-acetate,

m.p. l38-160 C. Anal. Calcd. 5

for C,,H,,,O,F,: C. 69.7l; H. 7.46; MW 378 AnaL Calut C. 158M! 378 for c,.u,,o,: c. 75.86; H, 9.70; MW 332.47

Found: C. 76.05; H, 9.76; MW 332 EXAMPLE 3 1 til-3,3, l7B-Diacetoxy-l3/3-ethyl-5-gonene dl-6,6-Difluorol 3fi-ethyll 7B-hydroxyl 7a-ethynyl-4-gonen- I 3-one ethylene ketal CH3 A. dl-3B-l7B-Diacetoxy-13B-ethyl-4,6gonadiene (L3H:

OH AcO I A620, A001, The product of step B was heated under reflux with 20 ml.

of acetic anhydride and 20. ml. of pyridine for 2 hours and poured onto 350 g. of ice to give the diacetate, which was (|)Ac Anal Calcd.

for C H on C. 73.76; H. 9J5

N O F ...M 40 NOB B Product of Step 0:

r CH1 dl-l8-Methyl-l9-nortestosterone (13.8 g.), (prepared by 0 COCH the method of Smith, J. Chem. Soc. 1964,4472 -4495),120 I 3 ml. of acetic anhydride, 60 ml. of acetyl chloride and 6 ml. of pyridine was heated under reflux for 2 hours; the volatiles were removed, and the residue was crystallized from methanol H to give 17.8 g. of dl-3B, l7B-diacetoxy-l3B-ethyl-4,6- gonadiene, m.p. l47-l49. 50 22 011.000 Anal. Calcd. I for c,.n,,o.= c.74.1e; n, 8.66; Mw. 372.49 F IJINO Found: C. 73.99; H, 8.70; MW, 372 2 (I315; B. dl-BB-Hydroxy-17B-acetoxy-l3fl-ethyl-5-gonene CH1 0 C OCH: CE

I 3 A CH2 p 0113000 I H F l 1M2 HO 7 The product of step C (7.2 g.) in ml. of methylene chloride was added slowly to a cooled (0 C.) solution of 4.67

The product of step A (10 g.) was dissolved in ml. of g. of nitrosyl tetrafluoroborate in ml. of glyme while a tetrahydrofuran, cooled to 0 C. and treated with 4.17 g. of total of 6.37 g. of nitrosyl fluoride was introduced in a slow cold sodium borohydride in ml. of ethanol; and the mix- 75 stream. The mixture was allowed to stand overnight, then it was poured into 500 ml. of brine, which was extracted twice G. dl-5a,6.6-Trifluoro-I 3B-ethylgona-3J7-dione with 100 ml. of methylene chloride. The organic solution was dried over sodium sulfate and the solvent evaporated to give an;

1 BBethyIgonane. The latter was dissolved in 30 ml. of benzene 5 6 and passed through 100 g. of neutral alumina of activity grade II III (containing 6 percent water) using 500 ml. of benzene as eluant. The steroid was rechromatographed using hexane, 3:] i by volume hexane: benzene, and benzene to give 6.94 g. of the dl-3B, l7B-diacetoxy-5a-fluorol3B-ethylgonan-6-one, which 10 was recrystallized from acetone-hexane, m.p. l50l54 C.

Anal. Calcd.

for C H O,F: C. 67.62; H. 8J4

Found: c. 67.82; H, 8.07

The diol from step F above (2.52 g.) was dissolved in 50 ml.

of acetone and stirred for 30.minutes with 6 ml. of 8N Cr0,.

E. dl-3B, 1 7B-Diacetoxy-5a,6,6-trifluorol 3B -ethylgonane The mixture was diluted with hot water togive a precipitate of 0 the dione in about 90 percent yield. Recrystallization from acetone-hexane gave colorless crystals, m.p. l89-l90 C.

OCOCHs AnaLCalcd.

for c..H,.F.o,= c. 66.65; H. 7.36 Found: c. 67.07; H. 7.6] H

H. dl-6,6-Difluorol 3B-ethyl-4-gona-3, l 7-dione The product of step D, above, (3.2 g.) in 40 ml. of methylene chloride and one ml. of water was agitated with 80 g. of sulfur tetrafluoride at 25 C. for 10 hours. To the mixture 35 H was added 225 ml. of methylene chloride; the methylene chloride solution was then washed with water, 5% NaHCO and brine and dried over MgSO,. The solvent was evaporated O and the product chromatographed on a F lon'sil column with 40 F: hexane and 5 percent acetonezhexane. The center cuts were combined and recrystallized from acetone (10 g.) and hexane (25 mm to give the "ifluomstemid 251 169-504 The dione obtained according to step G, above. (total of 3.8 g.) was dissolved in benzene and absorbed on a column of I 45 g. of neutral alumina of grade ill activity. After standing for 30 minutes, it was eluted with 1 liter of benzene. The benzene was evaporated and the residue crystallized from ml. of acetone/hexane to give 2.87 g. of 6,6-difluoro-l3B-ethyl-4- gona-3,l7-dione, m.p. l7l-172 C;

.Anal. Calcd. for C H RO C. 64.17; H. 7.73 Found: C. 64.37; H. 8.00

A solution of 2.45 g. of the preceding trifluorodiacetate from step E in 25 ml. of methanol and 3 ml. of concentrate HCI was heated to reflux for l hour. Water was added. and the h mixture was cooled and filtered. Crystallization from aqueous 70 acetone gave the diol in 98 percent yield, m.p. C. dec.

The above dione (2.5 g.) was heated under reflux (with a water separator) with 7.5 ml. ofvethylene glycol. 25 g. of oxal- 2:235: 65.89; H. 8A9 ic acid dihydrate and 100 ml. of benzene. Afier 6.5 hours, the

Found: C. 65.55; H. 8.66 75 mixture was extracted with 50 ml. of NaHCO soiution. 50 ml.

of water and dried over Masai The ketal had m.p. l86l93 C. The structure-was confirmed by infrared and the reaction monitored by TLC (using cyclohexane/ethyl acetate).

Anal. Calcd. for C, H F,O,:

Found:

C, 68.83; H. 7.70 C. 68.86; H, 7.93

J. dl-6,6Difluorol 3/3-ethyll 7B-hydroxyl 7a-ethynyl-4- gonen-3-one-3-ethylene ketal (1) R= CgH The subcutaneous progestational activity of 6,6-difluorol7B-hydroxy-l7a-ethynyl-4-estren-3-one ethylene ketal was determined by the Clauberg method as follows. immature female rabbits weighing 800 -l000 grams are estrogen-primed by means of daily subcutaneous doses of 5 g. of estradiol benzoate for 6 consecutive days. Beginning on the seventh day for 5 consecutive days, the new material of this invention is administered once daily in 0.5 percent tragacanth by subcutaneous injection. The rabbits are autopsied on the twelfth day. Sections of the uterine tissue are examined microscopicaliy and the uterine weight, ovarian weight and degree of progestational reaction in the endometrium are determined and compared with progesterone (total dose of 1 mg.

The oral progestational assay was performed using the method of McPhail; The Assay of Progestin, J. Physiol. (London) 83: -l56 (1934). immature female rabbits received 5 pg estradiol benzoate daily for 6 consecutive days (estrogen priming), followed by administration of the test material once daily in an aqueous vehicle for 5 consecutive days (days 7 -l l The rabbits were sacrificed on day l2. 6,6-Difluoro-l7 ,B-hydroxy-l7a-ethynylestr-4-en-3-one ethylene ketal was found to have abeut the same oral progestational activity as norethindrone.

The antiuterotrophic response of the test material was determined by the method of Dorfman et al.; Antiestrogen Assay of Neutral Steroids Administered by Gavage, Endocrinology 68: 43 -49( 1961 Intact weanling female Swiss- Webster mice were administered the test material daily by Gavage for 3 days in an aqueous vehicle. The mice simultaneously received a total dose of 0.4 g. estrone in sesame oil by injection. The mice were sacrificed on the day following the last treatment. The antiuterotrophic activity of 6,6-difluorol7B-hydroxy-l7a-ethynylestr-4-en-3-one ethylene ketal was equal to or larger than that of norethindrone.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Asteroid compound having the formula 2. 6,6-Difluorol 7B-hydroxyl 7a-ethynyl-4-estren-3-one ethylene ketal, the compound of claim 1 in which R is methyl.

3. 6,6-Difluorol 3B-ethyll 7B-hydroxyl 7a-ethylnyl-4- gonen-3-one ethylene ketal, the compound of claim 1 in which R is ethyl. 

2. 6,6-Difluoro-17 Beta -hydroxy-17 Alpha -ethynyl-4-estren-3-one ethylene ketal, the compound of claim 1 in which R is methyl.
 3. 6,6-Difluoro-13 Beta -ethyl-17 Beta -hydroxy-17 Alpha -ethylnyl-4-gonen-3-one ethylene ketal, the compound of claim 1 in which R is ethyl. 